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  • br Funding This work was supported by the

    2018-10-23


    Funding This work was supported by the NSF fellowshipDGE0909667 (P.J.H.) and the NIH fellowshipDA 035535 (P.J.H.), NIH grants DA038058 and DA012408 (A.G. & U.G.) as well as by the Danish Council for Independent Research Medical Sciences) (U.G.). N.G.C. was supported by the Training Program in Ion Channel and Transporter Biology (NIH T32NS007491). The funding sources had no role in the writing or submission of the manuscript. We have not been paid to write the article by any company or agency.
    Competing Interests
    Authors\' Contributions
    Acknowledgments
    Introduction Cystic fibrosis (CF), the most common life-shortening genetic disease affecting approximately 80,000 people worldwide (Bobadilla et al., 2002; The Molecular Genetic Epidemiology; Farrell, 2008; Rodrigues et al., 2009), is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The dominating clinical CF phenotype is the respiratory disease, being hallmarks of this disease the very thick mucus obstructing the airways, chronic inflammation and persistent infections mostly by Pseudomonas aeruginosa, which altogether lead to eventual impairment of respiratory function (Bell et al., 2015). Other CF symptoms include pancreatic dysfunction, elevated sweat electrolytes and male infertility, but the progressive loss of lung function remains the leading cause of morbidity and mortality (Bell et al., 2015). CFTR is an essential epithelial anion channel that regulates several other SCH 727965 manufacturer and transporters, altogether regulating ion homeostasis and water content of epithelia surfaces. This member of the ABC transporter family has been reported to host >1900 mutations, presumed to be CF-causing, albeit some still of unknown impact (Sosnay et al., 2013). Such genetic diversity makes the drug discovery based on protein rescue a huge task. Therefore, CFTR mutations are grouped into 6 functional classes, so as to apply the same CFTR-corrective therapy within each functional class to drastically downscale the drug discovery pipeline (for reviews see Bell et al., 2015; Amaral and Farinha, 2013). Notwithstanding, one single mutation — F508del, occurring in ~85% of CF patients in at least one allele and associated with severe CF —remains the most common CF mutation worldwide. F508del-CFTR is associated with defective traffic (Class II) which precludes it from reaching the cell surface [reviewed in (Amaral, 2004)]. The most attractive CFTR-modulator therapies involve: correctors to rescue F508del-CFTR to the cell surface and potentiators to restore CFTR mutants which exhibit a channel regulation defect (Class III). Potentiator ivacaftor, the first CFTR-targeting drug, was recently approved by FDA/EMA, albeit for a rare mutation — G551D (Ramsey et al., 2011) and for other Class III CFTR mutations (Van Goor et al., 2014; De Boeck et al., 2013), which, altogether only target ~5% of CF patients worldwide. For CF patients with the most frequent mutation F508del, the best investigational drug is VX-809 (or lumacaftor, Vertex), reported to rescue ~25% CFTR activity in F508del/F508del primary human bronchial (HBE) cells (Van Goor et al., 2011). Very recently, this investigational drug, in combination with ivacaftor, succeeded in showing significant efficacy in a Phase III clinical trial on F508del/F508del patients (Prease release), an achievement that will likely result in its FDA-approval. lumacaftor, plausibly acting by correcting the folding of a critical contact site in CFTR structure (Farinha et al., 2013), rescues the abnormal intracellular localization of F508del-CFTR to the cell surface, a traffic defect that is common to all Class II CFTR mutants. Our aim here was to assess efficacy of lumacaftor on other CFTR mutants with the same traffic defect as F508del (Class II (Amaral and Farinha, 2013)). Mutations tested here include: A561E, quite frequent in Southern-European and South-American countries like in Portugal (Mendes et al., 2003), Spain (Moya-Quiles et al., 2009) and Brazil (Servidoni et al., 2013) and N1303K, linked to ancient Mediterranean populations (Bobadilla et al., 2002). In addition we tested VX-809 in HBE cells bearing 2 nonsense mutations: G542X and Y1092X, both in heterozygosity with F508del.